Projects Offered

1 PhD project offered in the IPP summer call Molecular Mechanisms in Genome Stability & Gene Regulation

Scientific Background

The genomes of basically all living organisms on our planet are invaded by genetic elements called transposable elements (TEs). These TEs can be considered as parasites in our genome, although they also contribute to proper gene regulation and other aspects of normal cellular homeostasis. TEs tend to be most active in the germ cells, as their activity in these cells will be remembered in new generations. Hence, the control of these elements is particularly important in these cells. One of the major defense mechanisms that helps to keep TEs in check is known as the piRNA pathway. This mechanism is driven by small non-coding RNAs (piRNAs) that help to guide the effector proteins to their targets in a sequence specific manner. Hence, deciding which RNAs will be turned into piRNAs is a crucial step. How piRNA precursor transcripts are selected and processed is poorly understood. Also, these reactions tend to occur in subcellular regions known as condensates, or germ granules. This project will help address how subcellular organization, precursor selection and processing are interconnected.

PhD Project: Interactions between small RNAs and condensates

We use the nematode C. elegans to unravel the mechanisms that steer small RNA pathways in the germ cells. This system offers great opportunities in genetic manipulation and offers fast generations times, enabling experiments that are unthinkable in slower model systems such as that in mice. C. elegans also offers a unique view on how small RNA pathways evolve, and how they re-use already existing molecular machinery to change them into machines that enable the intricate genomic immune system that is described briefly above. At the same time, by understanding how ‘basic’ machinery can be re-purposed we also learn new things about that machinery itself, making this research truly fundamental, aiming to understand the molecular biology of the cell. 

In the past years we have made big steps in understanding how small RNAs can be made. We have identified novel enzymes and complexes that act together to stabilize and process specific transcripts into small RNAs, and where these machineries can come from. In the new PhD project we will aim to continue along these lines and look at novel factors that we have recently identified and how these affect the small RNA pathways. Some of these relate to germ granule formation, a type of condensate within the cell in which proteins and RNAs can become concentrated. The role of these is rather unclear, as is the role of condensates in cells in general. Using small RNA research we aim to answer questions like “what is the functional relevance of being enriched in a condensate?” and “how are these condensates regulated?”. Other factors related to the regulation of catalytic parts of the small RNA machinery more directly, such as a novel protein that regulates an RNA directed RNA polymerase. Finally, we aim to extend our recent findings on so-called Schlafen-domain enzymes into mammalian cells.

The exact PhD project will be a result of discussions between you and the group, aiming to match interest, expertise and feasibility as good as we possibly can.

If you are interested in this project, please select Ketting as your group preference in the IPP application platform.

Publications relevant to this project

Pereirinha J, Brehm M, Govind S, Busch A, Podvalnaya N, Seistrup AS, Delaney K, Steiner F, Konig J, Falk S, Ketting RF (2026) SLBP-independent control of maternal histone mRNA. BioRxiv Link 

Govind S, Ruppert S, Kirangwa J, Busetto V, Nischwitz E, Almeida M, Hellmann S, Witte H, Sommer RJ, Butter F, Falk S, Sarkies P, Ketting RF (2025) An Evolutionarily Conserved N-terminal Domain of RRF-3 Governs GTSF-1 Binding in Nematodes. BioRxiv Link 

Isolehto I, Pshanichnaya L, Páez-Moscoso DJ, Mager M, Seistrup AS, Schreier J, Hellmann S, Gaurav K, Kielisch F, Chen J, Stelzl LS, Ketting RF (2025) Proteolytic Control of an Auto-inhibitory Intrinsically Disordered Region Governs Small RNA Selectivity in Argonaute Proteins. BioRxiv Link

Schreier J, Pshanichnaya L, Kielisch F, Ketting RF (2025) A genetic framework for RNAi inheritance in Caenorhabditis elegans. EMBO Rep. 26, 4072–4099. Link

Podvalnaya N, Bronkhorst AW, Lichtenberger R, Hellmann S, Nischwitz E, Falk T, Karaulanov E, Butter F, Falk S, Ketting RF (2023) piRNA processing by a trimeric Schlafen-domain nuclease. Nature 622, 402–409. Link

Schreier J, Dietz S, Boermel M, Oorschot V, Seistrup AS, de Jesus Domingues AM, Bronkhorst AW, Nguyen DAH, Phillis S, Gleason EJ, L'Hernault SW, Phillips CM, Butter F, Ketting RF (2022) Membrane-associated cytoplasmic granules carrying the Argonaute protein WAGO-3 enable paternal epigenetic inheritance in Caenorhabditis elegans. Nat. Cell Biol. 24, 217–229. Link

Perez-Borrajero C, Podvalnaya N, Holleis K, Lichtenberger R, Karaulanov E, Simon B, Basquin J, Hennig J, Ketting RF, Falk S (2021) Structural basis of PETISCO complex assembly during piRNA biogenesis in C. elegans. Genes Dev. 35, 1304–1323. Link

Placentino M, de Jesus Domingues AM, Schreier J, Dietz S, Hellmann S, de Albuquerque BFM, Butter F, Ketting RF (2021) Intrinsically disordered protein PID-2 modulates Z granules and is required for heritable piRNA-induced silencing in the Caenorhabditis elegans embryo. EMBO J. 40, e105280. Link

Cordeiro Rodrigues RJ, de Jesus Domingues AM, Hellmann S, Dietz S, de Albuquerque BFM, Renz C, Ulrich HD, Sarkies P, Butter F, Ketting RF (2019) PETISCO is a novel protein complex required for 21U RNA biogenesis and embryonic viability. Genes Dev. 33. Link

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